CN100998566A - Temozolomide polylactic acid nano microsphere and preparation method thereof - Google Patents

Abstract

The invention relates to temozolomide biodegradable polymer nano-microspheres, preparations and preparation methods thereof, in particular to temozolomide polylactic acid nano-microspheres, preparations and preparation methods thereof. A temozolomide polylactic acid nanosphere prepared by ultrasonic emulsification solvent volatilization method and self-emulsification solvent diffusion method, which is a nanoparticle with temozolomide and polylactic acid as active ingredients, the average particle size is 10nm ~ 10μm, and the drug loading capacity is 1% to 32%, and has the function of sustained release and sustained release targeting. A temozolomide polylactic acid nano-microsphere preparation, which uses temozolomide poly-lactic acid nano-microspheres as an active ingredient and a temozolomide polylactic acid nano-microsphere preparation with a drug loading of 1% to 32%, and its dosage forms include injections, sterile packaging Freeze-dried powder injections, sustained-release pellets, discs and films. The preparation is suitable for malignant tumors, especially brain glioma, local chemotherapy such as intraoperative field application, stereotaxic intratumoral injection, or intravenous injection of slow-release and targeted chemotherapy.

Description

Temozolomide polylactic acid nano-microspheres and preparation and preparation method thereof

technical field

The invention relates to temozolomide biodegradable polymer nano-microspheres, preparations and preparation methods thereof, in particular to temozolomide polylactic acid nano-microspheres, preparations and preparation methods thereof.

Background technique

Temozolomide is a fat-soluble, water-insoluble broad-spectrum antineoplastic drug. It is currently the best single-drug chemotherapy drug for glioma. Its appearance is considered to be a major breakthrough in anti-brain tumor chemotherapy drugs in the past 40 years. At present, the dosage form of temozolomide is mainly oral capsules. After oral administration, temozolomide is widely distributed in the whole body after entering the body. It can pass through the blood-brain barrier. The half-life is about 1.3 hours, and there is no obvious first-pass effect. Malignant tumors such as glioma, degenerative astrocytoma, malignant melanoma, leukemia and lymphoma. Due to the rapid oral absorption and elimination of temozolomide and its short half-life, it is difficult to maintain a stable effective drug concentration in the brain. Usually, the dosage of oral capsules is relatively large, and certain toxic and side effects will occur during treatment, such as nausea, vomiting, constipation and bone marrow suppression. Clinical application has obvious limitations.

The polymer drug-loaded nano-microspheres have good penetration, sustained release and targeting properties, and can be used to prepare sustained-release targeted preparations of various drugs. Its application can not only enable the drug to have the targeting function of being able to cross the barriers such as the intercellular space and the blood-brain barrier and be absorbed by the lesion tissue and cells, but also enable the drug to improve the stability of the drug, which is beneficial to storage and transportation, and increases the drug's efficacy. Sustained release and low toxicity functions such as solubility and dissolution speed, prolonging the action time of drugs, reducing the dosage, enhancing drug efficacy, and reducing toxic and side effects are the most promising new drug delivery systems for various antitumor drugs. Obviously, making temozolomide into a polymer drug-loaded nanosphere formulation with sustained-release targeting function can effectively overcome the limitations of oral capsules and further improve drug performance.

Polylactic acid is a polymer material with excellent biocompatibility and biodegradability chemically synthesized from lactic acid monomer. Polylactic acid is insoluble in water and easily soluble in organic solvents such as acetone and ethanol. It is non-toxic, non-irritating and sensitizing to the human body, and has good anti-coagulant properties without causing inflammation. It undergoes enzymatic decomposition in the human body, and finally forms CO ₂ and H ₂ O. The intermediate product, lactic acid, is a product of glucose metabolism in the body and will not accumulate in vital organs. It is an ideal carrier material for drug delivery systems. At present, polylactic acid has been widely used as a drug carrier to make carrier drug preparations such as various microspheres, nanospheres, microcapsules, nanocapsules, and rod-shaped implants, but there is no preparation method for temozolomide lactic acid nanospheres and its preparations. literature reports.

Contents of the invention

The object of the present invention is to provide temozolomide polylactic acid nano-microspheres and preparations and preparation methods thereof for the above-mentioned disadvantages. The invention adopts ultrasonic emulsification solvent volatilization method and self-emulsification solvent diffusion method to prepare various temozolomide polylactic acid microspheres with an average particle size of 10nm to 10 μm and a drug loading of 1% to 32%, and the prepared temozolomide polylactic acid microspheres Made into injections with a drug loading of 1% to 32%, sterile subpackaged freeze-dried powder injections, sustained-release pellets, discs, and membranes, etc., used for intraoperative field application, stereotaxic intratumoral injection, etc. Local chemotherapy or intravenous injection of slow-release, targeted chemotherapy, using the prepared preparations in line with the biological characteristics of glioma and other tumors, long-acting slow-release and targeting in vivo, and good drug stability, etc. It can effectively avoid the toxic and side effects of systemic high-dose chemotherapy, solve the problem of surgical access, and improve the curative effect and quality of life of tumor patients such as brain glioma.

Temozolomide polylactic acid nano-microspheres, preparation and preparation method thereof are realized by adopting the following schemes:

Temozolomide-polylactic acid nanospheres are nanoparticles with temozolomide and polylactic acid as active ingredients. The average particle size is 10nm-10μm, the drug loading is 1%-32%, and it has slow-release and slow-release targeting functions.

The preparation method of temozolomide polylactic acid nano-microspheres is as follows:

1. The ultrasonic emulsification solvent evaporation method prepares temozolomide polylactic acid nano-microspheres, comprising the following steps: (1) temozolomide and polylactic acid are dissolved in a certain volume of hydrophobic solvent in a weight ratio of 2 to 200: 100 as an oil phase; ( 2) dissolving temozolomide and surfactant in a ratio of 1:0.1 to 10 by weight in a certain volume of deionized water as the water phase; (3) under ice-water bath conditions, pour the oil phase into the water phase for ultrasonic emulsification, and then Under the condition of 400-2000r/min, stir magnetically for 6-12 hours, until the hydrophobic organic solvents such as dichloromethane are completely volatilized, and the polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere emulsion dispersion system; (4) The dispersion system of the polylactic acid nano-microspheres of mozolomide is separated by centrifugation, ultrafiltration or dialysis, washed with deionized water to prepare poly-lactic acid nano-spheres of temozolomide, and dried to obtain poly-lactic acid nano-microspheres of temozolomide dry powder.

2. Preparation of temozolomide polylactic acid nanospheres by self-emulsifying solvent diffusion method, including the following steps: (1) dissolving temozolomide and polylactic acid in a weight ratio of 2 to 200:100 in a certain volume of acetone and ethanol and other hydrophilic binary components; Mixed solvent or acetone or acetonitrile as the oil phase; (2) dissolving temozolomide and surfactant in a ratio of 1:0.1 to 10 by weight in a certain volume of deionized water as the water phase; (3) slowly injecting the oil phase In the magnetically stirred water phase, fully stir for 12-24 hours under the condition of 400-2000r/min, so that the organic solvent in it is completely volatilized, and the polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere liquid emulsion dispersion system; (4) Centrifuging, ultrafiltration or dialysis separation of the polylactic acid nanosphere emulsion dispersion system of mozolomide, washing with deionized water, making polylactic acid nanospheres of temozolomide, and drying polylactic acid nanospheres dry powder of temozolomide.

Temozolomide polylactic acid nanosphere preparation is a temozolomide polylactic acid nanosphere preparation with temozolomide polylactic acid nanosphere as the active ingredient and a drug loading of 1% to 32%. , Sustained-release pellets, discs and membranes.

The preparation method of temozolomide polylactic acid nano-microsphere preparation is as follows:

1. the preparation method of temozolomide polylactic acid nano-microsphere preparation, comprises the steps: (1) the temozolomide polylactic acid nano-microsphere after the deionized water washing that preparation method of the present invention is made is washed with sterilized water for injection, then with temozolomide Polylactic acid nanospheres and sterilized water for injection are used as raw materials, and Temozolomide polylactic acid nanosphere injections are made through injection production processes such as raw material metering, uniform mixing, drug filling, γ-ray irradiation sterilization, quality inspection, and packaging; or Temozolomide polylactic acid nanospheres washed with sterilized water for injection are made by freeze-drying, weighing, γ-ray irradiation sterilization, drug filling into sterile bottles, capping, quality inspection, packaging and other aseptic powder production methods Temozolomide polylactic acid nano-microspheres aseptic packaging freeze-dried powder injection; (2) using the temozolomide polylactic acid nano-microspheres dry powder and sterile water for injection made by the preparation method of the present invention as raw materials, through the temozolomide polylactic acid nano-microspheres dry powder and An appropriate amount of sterilized water for injection is mixed into a paste, smeared on flat glass to dry, stripped, dosed, γ-ray irradiation sterilization, packaging and other production processes to make temozolomide polylactic acid nano-microsphere film; or through temozolomide polylactic acid nanosphere film Lactic acid nano-microsphere dry powder is placed into a mold, rolled at room temperature, demolded, divided doses, γ-ray irradiation sterilization, packaging and other production processes to make temozolomide-polylactic acid nano-microsphere film; (3) made by the preparation method of the present invention Temozolomide polylactic acid nano-microsphere dry powder and sterile water for injection are used as raw materials, relying on the excipient performance of polylactic acid microsphere itself, mixed with temozolomide polylactic acid nano-microsphere dry powder and about 10%-20% sterile water for injection to form a semi-dry Materials, granulation, tabletting, drying, gamma-ray irradiation sterilization, quality inspection, packaging and other production processes are used to make temozolomide polylactic acid nano-microsphere sustained-release pellets, discs and other preparations.

The relative molecular weight of the polylactic acid is 10,000-200,000.

The hydrophobic organic solvent is one of dichloromethane, chloroform, toluene and their mixed solvents, or other common hydrophobic organic solvents and their mixed solvents.

The hydrophilic binary mixed solvent is a binary mixed solvent of two solvents in acetone, ethanol, and methanol, or other common hydrophilic binary mixed solvents, and the weight ratio of the binary mixed solution is 1 ～100: 0～100.

The surfactant is one of poloxamer 188, polyethylene glycol, polyvinyl alcohol and hydroxypropyl methylcellulose, or other common surfactants.

The ultrasonic emulsification includes emulsification with different ultrasonic power and ultrasonic time, wherein the ultrasonic power is 0-1000 watts, and the ultrasonic time is 0.1-10 minutes.

The drying is freeze drying, vacuum drying, or other common drying methods.

The average particle size of the temozolomide polylactic acid microspheres is 10nm-10μm.

The temozolomide polylactic acid microspheres and the drug loading amount of the preparation are 1%-32%.

The temozolomide polylactic acid microsphere preparation includes injections, sterile subpackaged powder injections, slow-release pellets, discs and film materials.

In the temozolomide polylactic acid nano-microspheres and preparations and preparation methods thereof of the present invention, surfactants such as polylactic acid with different molecular weights and poloxamer 188, two preparation methods of temozolomide polylactic acid nano-microspheres and different temozolomide polylactic acid nano-particles are used. The preparation method of the microsphere preparation makes the prepared temozolomide polylactic acid nanospheres and preparations have the following characteristics: (1) the average particle size of the temozolomide polylactic acid microspheres can reach 10 nm to 10 μm, and the temozolomide polylactic acid microspheres prepared by the self-emulsifying solvent diffusion method The average particle size of microspheres can reach 10-100nm, and the average particle size of temozolomide-polylactic acid microspheres made by ultrasonic emulsification solvent evaporation can reach 100nm-10μm; (2) the drug-loading capacity of temozolomide-polylactic acid microspheres can reach 1%-32 %; (3) Temozolomide polylactic acid microspheres have good sustained-release performance, even the temozolomide polylactic acid microspheres with a particle size of 10-100nm can also meet the technical requirements for sustained-release drugs, and the temozolomide polylactic acid microspheres with a larger polylactic acid molecular weight The sustained release time of microspheres or temozolomide polylactic acid microspheres with larger particle size can be adjusted to about a few weeks to 1 year; (4) temozolomide polylactic acid microspheres with a particle size of about 10-50nm meet the requirements for penetrating the blood-brain barrier. , intercellular space and the technical requirements of the particle size of the targeted drug, which can be used to prepare various targeted drug preparations for intravenous injection and topical administration; (5) Temozolomide polylactic acid microsphere injection, and sustained-release pellets The drug loading capacity of preparations such as wafers, discs, and membranes can reach 1% to 32%, which can meet the requirements of local chemotherapy such as intraoperative field application in clinical operations, stereotaxic intratumoral injection, or intravenous injection sustained release, targeted chemotherapy, etc. The need for treatments.

Temozolomide polylactic acid nanospheres and preparations of the present invention and the self-emulsifying solvent diffusion method in the preparation method thereof can use binary mixed organic solvents such as acetone/ethanol instead of single organic solvents such as acetone and acetonitrile, and use acetone/ethanol binary mixed organic solvents For example, compared with the self-emulsifying solvent diffusion method of a single organic solvent, ethanol is more hydrophilic than acetone, and acetone has a higher affinity for polylactic acid than water. During the preparation process, with the addition of ethanol, it is beneficial for nano The rapid dispersion of emulsion droplets is conducive to the formation of nanoparticles, and even if the concentration of polylactic acid is large, agglomeration will not occur. The use of binary mixed organic solvents such as acetone/ethanol can effectively improve the dispersion effect of the emulsion and reduce the particle size of polylactic acid nano-microspheres. The temozolomide-polylactic acid nano-microspheres can be made by adopting a suitable acetone/ethanol ratio. The average particle size of the ball is more than 1 times smaller than that of acetone alone.

In the temozolomide polylactic acid nano-microspheres of the present invention and the preparation method thereof, the self-emulsifying solvent diffusion method adopts non-toxic ethanol to replace some toxic organic solvents such as acetone and acetonitrile, which can effectively reduce the amount of organic solvents such as acetone and acetonitrile. The residual amount of toxic organic solvents in the drug can reduce the volatilization of harmful organic solvents in the production process and the toxic and side effects of residual harmful organic solvents in the drug. Its development has created a new technology for the preparation of temozolomide polylactic acid nanospheres.

Detailed ways

The present invention will be further described below in conjunction with embodiment.

Example 1

(1) 50 mg of polylactic acid with relative molecular weight of 10000, 40000, 60000, 100000, 150000 and 200000 and 6 parts of 20 mg of temozolomide were respectively dissolved in 20 ml of dichloromethane as the oil phase; (2) 2 parts of 50 mg of Poloxamer 188, 2 parts of 200 mg of hydroxypropyl methylcellulose, and 2 parts of 500 mg of polyvinyl alcohol were respectively dissolved in 200 ml of deionized water as the water phase; (3) under 400W ultrasonic conditions, six The oil phases of polylactic acids with different molecular weights were slowly injected into the aqueous phase of six surfactants in sequence, and then magnetically stirred for 8 hours under the condition of 1000r/min to obtain six temozolomide polylactic acid nanospheres of polylactic acids with different molecular weights. Emulsion dispersion system; (4) The temozolomide polylactic acid nanosphere emulsion dispersion system of six polylactic acids with different molecular weights was centrifuged and washed with deionized water to obtain average particle sizes of 116, 146, 280, 967, and 4809 , 8362nm temozolomide polylactic acid drug-loaded nanospheres; (5) temozolomide polylactic acid nanospheres with 6 different particle sizes were washed with sterile water for injection, and then temozolomide polylactic acid nanospheres with 6 different particle sizes and Sterile water for injection is used as the raw material, and temozolomide polylactic acid nano-microsphere injections of 6 different particle sizes are made through the injection production processes such as raw material metering, uniform mixing, drug filling, gamma ray irradiation sterilization, quality inspection, and packaging; or Six kinds of temozolomide polylactic acid nanospheres with different particle sizes were prepared by aseptic powder production methods such as freeze-drying, weighing, gamma-ray irradiation sterilization, drug filling into sterile bottles, capping, quality inspection, and packaging. Temozolomide polylactic acid nanospheres with different particle sizes are sterile subpackaged freeze-dried powder injections.

Example 2

(1) 10, 25, 50, 70 mg of temozolomide and 4 parts of 50 mg of polylactic acid were dissolved in 20 ml of chloroform as the oil phase; (2) 30, 60, 100, 180 mg of poloxamer 188 were dissolved in 4 parts of 100ml of deionized water were used as the water phase; (3) 4 different oil phases were slowly injected into 4 different concentrations of poloxamer 188 water phases with a syringe in turn, and ultrasonically emulsified under the condition of 600W in an ice-water bath 1, 5, 5, and 10 minutes, and then magnetically stirred for 6 hours under the condition of 2000r/min to obtain four temozolomide polylactic acid nanosphere emulsion dispersion systems; (4) disperse the four temozolomide polylactic acid nanosphere emulsions The system was separated by centrifugation and washed with sterilized water for injection to prepare four kinds of temozolomide polylactic acid drug-loaded nanospheres with drug loadings of 4.6%, 13.6%, 27%, and 32% respectively; (5) washing with deionized water The temozolomide polylactic acid drug-loaded nanospheres were freeze-dried to make three kinds of temozolomide polylactic acid nanosphere freeze-dried powders with different drug loadings, and the prepared temozolomide polylactic acid nanosphere dry powder and sterile water for injection were used as raw materials. Temozolomide polylactic acid nano-microsphere freeze-dried powder and appropriate amount of sterile water for injection are mixed to form a paste, smeared on flat glass for drying, stripping, sub-dose, γ-ray irradiation sterilization, packaging and other production processes to make drug loading Respectively 4.6%, 13.6%, 27%, 32% temozolomide polylactic acid nano-microsphere film; or through temozolomide polylactic acid nano-microsphere dry powder into the mold, normal temperature calendering, demoulding, divided doses, gamma ray irradiation Temozolomide polylactic acid nano-microspheres with drug loadings of 4.6%, 27%, and 32% were prepared by bacteria, packaging and other production processes.

Example 3

(1) Dissolve 50 mg of temozolomide and 50 mg of polylactic acid in 20 ml of toluene as the oil phase; (2) dissolve 20 mg of Poloxamer 188 in 400 ml of deionized water as the water phase; Slowly inject the water phase, ultrasonically emulsify under the condition of 200W in the ice-water bath, and then magnetically stir under the condition of 400r/min for 10 hours to obtain the temozolomide polylactic acid nanosphere emulsion dispersion system; (4) the temozolomide polylactic acid nanosphere The emulsion dispersion system was subjected to centrifugal ultrafiltration at 20000r/min, and washed with deionized water to obtain temozolomide polylactic acid drug-loaded nanospheres; Lactic acid nanosphere freeze-dried powder is made of temozolomide polylactic acid nanosphere dry powder and sterile water for injection, relying on the excipient performance of polylactic acid microsphere itself, through temozolomide polylactic acid nanosphere dry powder and about 10%-20% Sterilized water for injection is mixed into semi-dry materials, granulated, compressed into tablets, dried, γ-ray irradiation sterilization, quality inspection, packaging and other production processes to make temozolomide polylactic acid nano-microsphere sustained-release pellets, discs and other preparations.

Example 4

(1) temozolomide 30mg and polylactic acid 50mg are dissolved in 20ml of dichloromethane and toluene mixed solution as oil phase; (2) Poloxamer 188 10mg is dissolved in 150ml of deionized water respectively as water phase; (3 ) Under the ultrasonic condition of 1000W, inject the oil phase into the water phase slowly with a syringe respectively, and then magnetically stir for 12 hours under the condition of 1500r/min to obtain the temozolomide polylactic acid nano-microsphere emulsion dispersion system; (4) the temozolomide polylactic acid The nano-microsphere emulsion dispersion system is separated by dialysis and washed with deionized water to prepare temozolomide-polylactic acid drug-loaded nano-spheres; (5) vacuum-dry the temozolomide-polylactic acid-loaded nano-spheres after deionized water washing to prepare temozolomide polylactic acid-loaded nanospheres. Lactic acid nano-microsphere dry powder, made of temozolomide polylactic acid nano-microsphere dry powder and sterile water for injection as raw materials, mixed with temozolomide polylactic acid nano-microsphere freeze-dried powder and appropriate amount of sterile water for injection to form a paste, and spread it on the plate Temozolomide polylactic acid nano-microsphere film is made by drying on glass, demoulding, dividing dosage, γ-ray irradiation sterilization, packaging and other production processes; or put the dry powder of polylactic acid nano-microsphere into the mold, calender at room temperature, and release the mold , sub-dose, γ-ray irradiation sterilization, packaging and other production processes to make temozolomide polylactic acid nano-microsphere film agent.

Example 5

(1) 30 mg of temozolomide and 50 mg of polylactic acid are respectively dissolved in 20 ml of acetone: ethanol with a weight ratio of 9:0, 7:2, 4:5 in the binary mixed solution of acetone and ethanol as the oil phase; (2) Three parts of 100 mg of poloxamer 188 were respectively dissolved in 200 ml of deionized water as the water phase; (3) 3 parts of the oil phase were slowly injected into the 3 parts of the water phase with magnetic stirring, and fully stirred under the condition of 2000r/min for 12 hours, the organic solvent therein is completely volatilized, and the polylactic acid nanospheres solidify to form a temozolomide polylactic acid nanosphere liquid emulsion dispersion system; (4) the temozolomide polylactic acid nanosphere emulsion dispersion system is separated by high-speed centrifugation, deionized water Wash to obtain temozolomide polylactic acid drug-loaded nanospheres with an average particle size of 46nm, 27nm, and 9nm; (5) wash the temozolomide polylactic acid nanospheres with 3 different particle sizes with sterile water for injection, and then wash them with 3 Temozolomide polylactic acid nanospheres with different particle sizes and sterilized water for injection are used as raw materials, and three different types of injections are made through raw material metering, uniform mixing, drug filling, γ-ray irradiation sterilization, quality inspection, and packaging. Temozolomide polylactic acid nanosphere injection with particle size; or three different particle sizes of temozolomide polylactic acid nanospheres were freeze-dried, weighed, γ-ray irradiation sterilized, the drug was filled into sterile bottles, capped, and mass-produced. Three kinds of temozolomide polylactic acid nanospheres with different particle sizes were prepared by aseptic powder production methods such as inspection and packaging.

Example 6

(1) Temozolomide 15mg and polylactic acid 10mg are dissolved in 20ml of acetone and ethanol binary mixed solution as oil phase; (2) Poloxamer 188 5mg is dissolved in 150ml of deionized water as water phase; (3) Slowly inject the oil phase into the magnetically stirred water phase, and fully stir for 16 hours under the condition of 1500r/min, so that the organic solvent in it is completely volatilized, and the polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere liquid emulsion dispersion system (4) the temozolomide polylactic acid nano-microsphere emulsion dispersion system is subjected to centrifugal ultrafiltration and washed with deionized water to obtain temozolomide polylactic acid drug-loaded nano-microspheres with an average particle diameter of 61nm; (5) after washing with deionized water Temozolomide polylactic acid drug-loaded nanospheres were freeze-dried to make temozolomide polylactic acid nanospheres freeze-dried powder. The prepared temozolomide polylactic acid nanospheres dry powder and sterile water for injection were used as raw materials to freeze-dry temozolomide polylactic acid nanospheres. Powder and appropriate amount of sterile water for injection are mixed into a paste, smeared on flat glass for drying, stripped, dosed, γ-ray irradiation sterilization, packaging and other production processes to make temozolomide polylactic acid nano-microsphere film; or through Temozolomide polylactic acid nano-microspheres dry powder is placed into a mold, rolled at room temperature, demolded, divided doses, gamma-ray irradiation sterilization, packaging and other production processes to make temozolomide polylactic acid nano-microspheres film agent.

Example 7

(1) Temozolomide 10mg and polylactic acid 20mg are dissolved in 20ml of acetone and ethanol binary mixed solution as oil phase; (2) Poloxamer 188 20mg is dissolved in 200ml of deionized water as water phase; (3) Slowly inject the oil phase into the magnetically stirred water phase, and fully stir for 24 hours under the condition of 800r/min, so that the organic solvent in it is completely volatilized, and the polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere liquid emulsion dispersion system (4) the temozolomide polylactic acid nano-microsphere emulsion dispersion system is separated through the dialysis zone, and washed with deionized water to prepare the temozolomide polylactic acid drug-loaded nano-microspheres with an average particle diameter of 37nm and a drug loading of 14.6%; (5 ) Freeze-dry the temozolomide polylactic acid drug-loaded nanospheres after washing with deionized water to make temozolomide polylactic acid nanosphere freeze-dried powder, use temozolomide polylactic acid nanosphere dry powder and sterile water for injection as raw materials, rely on polylactic acid microspheres Self-excipient performance, mixed with temozolomide polylactic acid nano-microspheres dry powder and about 10%-20% sterile water for injection into semi-dry materials, granulation, tabletting, drying, γ-ray irradiation sterilization, quality inspection, packaging Preparations such as temozolomide polylactic acid nano-microsphere sustained-release pellets and discs with a drug loading of 14.6% were made by other production processes.

Example 8

(1) Temozolomide 15mg and polylactic acid 10mg are dissolved in 20ml of acetone and methanol binary mixed solution as oil phase; (2) Poloxamer 188 5mg is dissolved in 150ml of deionized water as water phase; (3) Slowly inject the oil phase into the magnetically stirred water phase, and fully stir for 16 hours under the condition of 1500r/min, so that the organic solvent in it is completely volatilized, and the polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere liquid emulsion dispersion system (4) the temozolomide polylactic acid nano-microsphere emulsion dispersion system is subjected to centrifugal ultrafiltration and washed with deionized water to obtain temozolomide polylactic acid drug-loaded nano-microspheres with an average particle diameter of 53nm; (5) after washing with deionized water temozolomide polylactic acid drug-loaded nanospheres made into temozolomide polylactic acid nanosphere injections, or freeze-dried to make temozolomide polylactic acid nanospheres freeze-dried powder, the prepared temozolomide polylactic acid nanospheres dry powder and sterile water for injection are The raw material is made by mixing temozolomide polylactic acid nano-microsphere freeze-dried powder and an appropriate amount of sterile water for injection into a paste, smearing it on a flat glass for drying, stripping, dividing doses, γ-ray irradiation sterilization, packaging and other production processes. Temozolomide polylactic acid nano-microsphere film agent; or temozolomide polylactic acid nano-microspheres are made by placing the dry powder of temozolomide polylactic acid nano-microspheres into a mold, rolling at room temperature, demolding, dividing doses, γ-ray irradiation sterilization, packaging and other production processes film agent.

Example 9

(1) Temozolomide 10mg and polylactic acid 20mg are dissolved in 20ml of acetone and methanol binary mixed solution as oil phase; (2) Poloxamer 188 20mg is dissolved in 200ml of deionized water as water phase; (3) Slowly inject the oil phase into the magnetically stirred water phase, and fully stir for 24 hours under the condition of 800r/min, so that the organic solvent in it is completely volatilized, and the polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere liquid emulsion dispersion system (4) the temozolomide polylactic acid nano-microsphere emulsion dispersion system is separated through the dialysis zone, and washed with deionized water to prepare the temozolomide polylactic acid drug-loaded nano-microspheres with an average particle diameter of 43nm; (5) after washing with deionized water Temozolomide polylactic acid drug-loaded nanospheres were freeze-dried to make temozolomide polylactic acid nanosphere freeze-dried powder, using temozolomide polylactic acid nanosphere dry powder and sterile water for injection as raw materials, relying on the excipient performance of polylactic acid microspheres, through Temozolomide polylactic acid nano-microspheres dry powder and about 10%-20% sterile water for injection are mixed into semi-dry materials, granulated, tabletted, dried, γ-ray irradiation sterilization, quality inspection, packaging and other production processes to make Temozolomide poly Lactic acid nano-microsphere sustained-release pellets, discs and other preparations.

Example 10

(1) 15 mg of temozolomide and 10 mg of polylactic acid were dissolved in 20 ml of acetone as the oil phase; (2) 188 5 mg of poloxamer was dissolved in 150 ml of deionized water as the water phase; (3) the oil phase was slowly injected into the magnetic In the stirred water phase, under the condition of 1500r/min, fully stir for 16 hours, so that the organic solvent therein is completely volatilized, and the polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere liquid emulsion dispersion system; (4) temozolomide The polylactic acid nano-microsphere emulsion dispersion system is subjected to centrifugal ultrafiltration and washed with deionized water to obtain temozolomide polylactic acid drug-loaded nano-microspheres with an average particle size of 58 nm; Nanospheres are made into temozolomide polylactic acid nanosphere injection, or freeze-dried to make temozolomide polylactic acid nanosphere freeze-dried powder, using the prepared temozolomide polylactic acid nanosphere dry powder and sterile water for injection as raw materials, through temozolomide polylactic acid Nano-microsphere freeze-dried powder and appropriate amount of sterilized water for injection are mixed into a paste, smeared on flat glass for drying, stripping, dose-dividing, γ-ray irradiation sterilization, packaging and other production processes to make temozolomide polylactic acid nano-spheres film; or the temozolomide polylactic acid nanosphere film is made by putting the dry powder of polylactic acid nanospheres into a mold, calendering at room temperature, demolding, dividing doses, sterilizing by gamma ray irradiation, and packaging.

Example 11

(1) Dissolve 10 mg of temozolomide and 20 mg of polylactic acid in 20 ml of acetonitrile as the oil phase; (2) dissolve 20 mg of Poloxamer 188 in 200 ml of deionized water as the water phase; (3) slowly inject the oil phase In the aqueous phase of magnetic stirring, under the condition of 800r/min, fully stir for 24 hours, make the organic solvent therein volatilize completely, the polylactic acid nano-microsphere solidifies, forms the temozolomide polylactic acid nano-microsphere liquid emulsion dispersion system; (4) will Temozolomide polylactic acid nano-microsphere emulsion dispersion system is separated by dialysis zone, and washed with deionized water to prepare temozolomide polylactic acid drug-loaded nano-microspheres with an average particle diameter of 49nm; Temozolomide polylactic acid nanosphere freeze-dried powder is prepared by freeze-drying drug nanospheres, using temozolomide polylactic acid nanosphere dry powder and sterile water for injection as raw materials, relying on the excipient performance of polylactic acid microspheres, through temozolomide polylactic acid nanosphere Dry spherical powder and about 10%-20% sterile water for injection are mixed into semi-dry materials, granulated, tabletted, dried, γ-ray irradiation sterilization, quality inspection, packaging and other production processes to make temozolomide polylactic acid nano-microspheres. Release pellets, discs and other preparations.

The particle size distribution of the temozolomide polylactic acid nano-microspheres in each of the above examples was detected by a Zetasizer 3000HSA laser particle size analyzer from Malven, UK.

Claims (10)

1. A temozolomide polylactic acid nanosphere, characterized in that it is a nanoparticle of temozolomide and polylactic acid as active ingredients, its average particle size is 10nm～10μm, the drug loading is 1%～32%, and it has sustained release, Slow-release targeted function. 2. The preparation method of temozolomide polylactic acid nanospheres according to claim 1, characterized in that the preparation of temozolomide polylactic acid nanospheres by ultrasonic emulsification solvent volatilization method comprises the following steps: (1) proportioning temozolomide and polylactic acid by weight 2～200:100 is dissolved in a certain volume of hydrophobic solvent as an oil phase; (2) temozolomide and a surfactant are dissolved in a certain volume of deionized water in a weight ratio of 1:0.1～10 as an aqueous phase; (3 ) under ice-water bath conditions, pour the oil phase into the water phase for ultrasonic emulsification. Ultrasonic emulsification includes emulsification with different ultrasonic power and ultrasonic time, wherein the ultrasonic power is 0-1000 watts, the ultrasonic time is 0.1-10 minutes, and then at 400- Under the condition of 2000r/min, stir magnetically for 6 to 12 hours until the hydrophobic organic solvent therein is completely volatilized and the polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere emulsion dispersion system; (4) mozolomide polylactic acid The nano-microsphere emulsion dispersion system is separated by centrifugation, ultrafiltration or dialysis, washed with deionized water to prepare temozolomide-polylactic acid nano-microspheres, and dried to prepare temozolomide-polylactic acid nano-microspheres dry powder. 3. The preparation method of temozolomide polylactic acid nano-microsphere preparation according to claim 2, characterized in that said hydrophobic organic solvent is one of dichloromethane, chloroform, toluene and its mixed solvent, also It can be other common hydrophobic organic solvents and their mixed solvents. 4. The preparation method of temozolomide polylactic acid nano-microsphere preparation according to claim 2, characterized in that the ultrasonic emulsification includes emulsification with different ultrasonic power and ultrasonic time, wherein the ultrasonic power is 0-1000 watts, and the ultrasonic time is 0.1 to 10 minutes. 5. The method for preparing temozolomide polylactic acid nanospheres according to claim 1, characterized in that the self-emulsifying solvent diffusion method is used to prepare temozolomide polylactic acid nanospheres, comprising the following steps: (1) mixing temozolomide and polylactic acid in a weight ratio 2～200:100 dissolved in a certain volume of hydrophilic binary mixed solvents such as acetone and ethanol or acetone or acetonitrile as the oil phase; Use a certain volume of deionized water as the water phase; (3) slowly inject the oil phase into the magnetically stirred water phase, and fully stir for 12-24 hours under the condition of 400-2000r/min, so that the organic solvent therein is completely volatilized, The polylactic acid nanospheres are solidified to form a temozolomide polylactic acid nanosphere liquid emulsion dispersion system; (4) the mozolomide polylactic acid nanosphere emulsion dispersion system is subjected to centrifugation, ultrafiltration or dialysis separation, and deionized water is washed to prepare Temozolomide polylactic acid nano-microspheres are dried to make temozolomide polylactic acid nano-microspheres dry powder. 6. The preparation method of temozolomide polylactic acid nano-microsphere preparation according to claim 5, characterized in that said hydrophilic organic solvent is acetone, ethanol, methanol binary mixed solvent of two solvents or acetone or ethyl alcohol Qing, or other common hydrophilic organic solvent mixed solvents, the weight ratio of the binary mixed solution is 1-100:0-100. 7. The preparation method of temozolomide polylactic acid nano-microsphere preparation according to claim 2 or 5, characterized in that said surfactant is poloxamer 188, polyethylene glycol, polyvinyl alcohol and hydroxypropyl methyl A kind of base cellulose and its mixture, also can be other common surfactants. 8. The preparation method of temozolomide polylactic acid nano-microsphere preparation according to claim 2 or 5, characterized in that the relative molecular weight of the polylactic acid is 10,000-200,000. 9. A temozolomide polylactic acid nano-microsphere preparation, which is characterized in that the temozolomide polylactic acid nano-microsphere is used as an active ingredient, and the drug-loading amount is 1% to 32% of the temozolomide polylactic acid nano-microsphere preparation. Freeze-dried powder for injection, sustained-release pellets, disks and membranes. 10. The preparation method of the temozolomide polylactic acid nano-microsphere preparation according to claim 9, which is characterized in that it comprises the following steps: (1) washing the temozolomide polylactic acid nano-microsphere with sterile water for injection, and then washing the temozolomide polylactic acid nano-microsphere Ball and sterilized water for injection are used as raw materials, and temozolomide polylactic acid nano-microsphere injection is made through injection production processes such as raw material metering, uniform mixing, drug filling, γ-ray irradiation sterilization, quality inspection, and packaging; or sterilized injection The temozolomide polylactic acid nanospheres washed with water are freeze-dried, weighed, gamma-ray irradiated and sterilized, the drug is filled into sterile bottles, crimped caps, quality inspection, packaging and other aseptic powder production methods to make temozolomide polylactic acid nanoparticles. Microsphere sterile sub-packaging freeze-dried powder injection; (2) using temozolomide polylactic acid nano-microsphere dry powder and sterile water for injection as raw materials, mixing temozolomide polylactic acid nano-microsphere dry powder and appropriate amount of sterile water for injection into a paste, Apply on flat glass to make temozolomide polylactic acid nano-microsphere film agent through production processes such as drying, stripping, dividing dosage, gamma-ray irradiation sterilization, packaging, etc.; Temozolomide polylactic acid nano-microsphere film is made by production processes such as mold release, dosage, γ-ray irradiation sterilization, and packaging; (3) Temozolomide polylactic acid nano-microsphere dry powder and sterile water for injection are used as raw materials, relying on poly The excipient properties of lactic acid microspheres are mixed into semi-dry materials by temozolomide polylactic acid nano-microspheres dry powder and about 10%-20% sterile water for injection, granulating, tableting, drying, γ-ray irradiation sterilization, quality Temozolomide polylactic acid nano-microsphere sustained-release pellets and disc preparations are made by inspection, packaging and other production processes.